CABALA_Diet & Health

CABALA_DIET&HEALTH aimed to demonstrate that diet-microbiome interactions in the gut determine circulating bile acid (CBA) profiles and their physiological effects. Our overarching objective was to provide evidence in humans, that CBA may be considered modifiable biomarkers of cardiovascular or metabolic health and disease risk, which are determined by the gut microbiota and respond to diet and life-style intervention. The project has published new analytical methodologies, analyzed data and samples from existing/ongoing studies, including the DIRECT-PLUS study in Israel, developed new pre-clinical in vitro models for measuring CBA cell signaling and completed the CABALA_diet&health dietary intervention study in Reading, UK. It has also generated new models correlating CBA with gut microbiota composition (FEM, USDI), with dietary intake, exercise and with clinical markers of cardiovascular disease (CVD) risk. It has demonstrated that diet, both in chronic and acute postprandial settings influence CBA profiles and that total CBA concentrations and profiles of CBA are inversely related with specific CVD risk biomarkers at a population level (RoCAV study, Varese Italy). CABALA_diet&health has demonstrated and developed new cell based reporter systems at UCC, Ireland, which confirm that different CBA and profiles of CBA can regulate host physiological processes involved in inflammatory and metabolic pathways which govern CVD and metabolic disease risk and moreover, we have shown that major perturbation of the gut microbiota, via diet (DIRECT-PLUS green-MED diet), surgery (three different common bariatric surgeries) and autologous faecal microbiome transplant (aFMT) can modulate CBA, biomarkers of CVD risk and body weight in humans. From our observations we can also propose that global BA species diversity is associated with metabolic and immune health, and that reduced diversity is associated with inflammatory related disease. This project, therefore, has provided strong evidence in humans, that CBA concentrations may be a biomarker of health, modified by diet, exercise and the gut microbiota. It has also provided support that microbiota BA metabolism may play an important mechanistic role in mediating the health effects of the Mediterranean style diet and bioactive foods including oats, apples and probiotics (Limosilactobacillus reuteri NCIMB 30242 ). Further, we have provided new evidence in humans, that the gut microbiota and its BA metabolism, may be an active driver of diet induced weight management, retreat of diabetes upon surgery and major dietary intervention, and that aFMT of a green-MED diet modified microbiome can reduce the risk of weight regain and metabolic rebound following successful diet induced weight loss. Together, data from the CABALA_diet&health projects support the notion that the gut microbiota is not a passive by-stander in obesity and metabolic disease, but an active player in metabolic health. Furthermore, we have also shown that diet and medical interventions known to reduce body weight and improve markers of metabolic disease risk do so in part through their interactions with the gut microbiota and that microbial BA metabolism contributes mechanistically to metabolic health across Domains of life. 

CABALA_diet&health therefore provides fundamental new insights into how diet, through the gut microbiota, can shape metabolic and inflammatory related chronic disease risk. This supports JPI-HDHL efforts to tackle the societal challenge of nutrition and health. Specifically, by demonstrating that total CBA concentrations and  profiles are related to CVD markers, we provide supportive human observational data of their health biomarker status. By demonstrating that foods and diet, especially healthy high polyphenol diets can regulate total CBA in the long term (DIRECT-PLUS study) and postprandially on an individual basis, we provide support for population level interventions with foods and diets rich in polyphenols and fiber and providescientific support for existing healthy eating guidelines based on the Mediterranean style diet. Similarly, by demonstrating that the gut microbiome, which regulates both the size of the BA pool systemically and the profile of individual BA species in circulation and in faeces, contributes directly to weight loss and improved metabolic health (DIRECT-PLUS ), we provide new supportive data in humans, that microbiome targeted strategies have significant potential to tackle the global burden of overweight, obesity and the diseases of obesity. Healthy dietary guidelines, especially those targeting metabolic and cardiovascular disease, are well established throughout the world but translation to individual lifestyles remains a challenge. Part of the problem is lack of mechanistic understanding of how healthy foods and diets translate into physiological effects in the human body. This has challenged medical uptake of nutrition as an efficacious intervention or even preventative strategy, and left room for confused and contradictory messaging in the general media, contributing to poor uptake of healthy diets at the population level. Similarly, without sound scientific basis of how healthy foods regulate host physiology, the food industry has struggled to provide nutritious foods to serve the challenges of modern lifestyles. However, foods and medical intervention strategies for shaping the gut microbiota are well established, and by providing new insight into how microbiome modulation can shape CBA profiles and total concentrations, and concomitantly influence host physiology, CABALA_diet&health has contributed significantly to providing a rational basis for designing the next generation of functional foods. Future work should help fill gaps in nutrient:nutrient interactions in the gut and how they influence the gut microbiome and BA metabolism; new bioinformatics tools to link new or dual function microbial enzymes to specific chemical reactions in BA metabolism, and a more personalized, genotype based approach towards CBA:BA receptor interactions; and broader application of nutri-kinetics based approaches to demonstrating how foods and diets modulate microbially derived metabolites capable of regulating human metabolic and inflammatory pathways and shown in animal studies to determine chronic disease risk and immune-resilience in the face of pathogen invasion.